The cellular and molecular pathways involved in the regulatory effects of proinflammatory and immunoregulatory cytokines and chemokines on human immunodeficiency virus (HIV) replication as well as the effect of HIV on the ability of CD4+ T cells to respond to certain cytokines were investigated. Levels of in vitro HIV replication in CD4+ peripheral blood mononuclear cells (PBMC) from HIV-infected subjects was found to reflect the net regulatory effects of endogenous HIV-suppressing beta chemokines (MIP-1alpha, MIP-1beta, RANTES) and endogenous HIV-inducing proinflammatory cytokines (TNF-alpha, IL-1beta). Analysis of the ability of various PBMC subsets to produce beta chemokines and to suppress HIV replication in vitro is being conducted. A metalloproteinase inhibitor known to block the secretion of TNF-alpha was found to dramatically suppress HIV replication in chronically HIV-infected cell lines, acutely HIV-infected PBMC and in PBMC from HIV-infected subjects; this treatment had no detrimental effect on cellular activation or proliferation. Similarly, a novel aminosterol was found to dramatically inhibit HIV replication in these same 3 cell populations as well as in acutely simian immunodeficiency virus (SIV)-infected PBMC from macaques. An efficacy study of this aminosterol in SIV-infected macaques is ongoing. Finally, preliminary studies suggest an inhibitory effect of HIV gp160-mediated CD4 crosslinking on the ability of T cells to activate DNA binding of STATs (signal transducers and activators of transcription) upon interleukin (IL)-2 receptor occupancy. These studies demonstrate the complex interactions between cytokines and chemokines and HIV replication. In addition, several novel agents which interfere with cellular processes or factors important for the efficient replication of HIV have demonstrated effective HIV-inhibitory activity in vitro.